310 results on '"Tetsuo Ushiku"'
Search Results
2. Loss of viral genome with altered immune microenvironment during tumour progression of <scp>Epstein‐Barr virus</scp> ‐associated gastric carcinoma
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Atsushi Kondo, Aya Shinozaki‐Ushiku, Hirofumi Rokutan, Akiko Kunita, Masako Ikemura, Hiroharu Yamashita, Yasuyuki Seto, Genta Nagae, Kenji Tatsuno, Hiroyuki Aburatani, Daizo Koinuma, and Tetsuo Ushiku
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Pathology and Forensic Medicine - Published
- 2023
3. Multiancestry genomic and transcriptomic analysis of gastric cancer
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Yasushi Totoki, Mihoko Saito-Adachi, Yuichi Shiraishi, Daisuke Komura, Hiromi Nakamura, Akihiro Suzuki, Kenji Tatsuno, Hirofumi Rokutan, Natsuko Hama, Shogo Yamamoto, Hanako Ono, Yasuhito Arai, Fumie Hosoda, Hiroto Katoh, Kenichi Chiba, Naoko Iida, Genta Nagae, Hiroki Ueda, Chen Shihang, Shigeki Sekine, Hiroyuki Abe, Sachiyo Nomura, Tetsuya Matsuura, Eiji Sakai, Takashi Ohshima, Yasushi Rino, Khay Guan Yeoh, Jimmy So, Kaushal Sanghvi, Richie Soong, Akihiko Fukagawa, Shinichi Yachida, Mamoru Kato, Yasuyuki Seto, Tetsuo Ushiku, Atsushi Nakajima, Hitoshi Katai, Patrick Tan, Shumpei Ishikawa, Hiroyuki Aburatani, and Tatsuhiro Shibata
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Genetics - Published
- 2023
4. Metastasis of Ovarian Cancer to the Descending Colon
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Kentaro Abe, Hiroyuki Anzai, Satoko Eguchi, Masako Ikemura, Aya Shinozaki-Ushiku, Takahide Shinagawa, Hirofumi Sonoda, Yuichiro Yoshioka, Yuzo Nagai, Shinya Abe, Hiroyuki Matsuzaki, Yuichiro Yokoyama, Shigenobu Emoto, Koji Murono, Kazuhito Sasaki, Hiroaki Nozawa, Tetsuo Ushiku, and Soichiro Ishihara
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Gastroenterology - Abstract
Colonic metastasis from ovarian cancer is extremely rare, with only seven reported cases. A 77-year-old woman who had previously undergone surgery for ovarian cancer was admitted to a local hospital with anal bleeding. Histopathological analysis confirmed the presence of adenocarcinoma. Colonoscopy revealed a descending colon tumor. The patient was diagnosed with Union for International Cancer Control T3N0M0 descending colon cancer or colon metastasis of the ovarian cancer. Laparoscopic left colectomy was performed; intraoperative frozen section diagnosis confirmed metastasis from ovarian cancer, and the absence of invasion to the serosal surface suggested hematogenous metastasis. This is the first case of colonic metastasis from ovarian cancer that was diagnosed using an intraoperative frozen section and laparoscopically treated.
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- 2023
5. Application of organoid culture from <scp>HPV18</scp> ‐positive small cell carcinoma of the uterine cervix for precision medicine
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Misako Kusakabe, Ayumi Taguchi, Michihiro Tanikawa, Daisuke Hoshi, Saki Tsuchimochi, Xi Qian, Yusuke Toyohara, Akira Kawata, Ryota Wagatsuma, Kohei Yamaguchi, Yoko Yamamoto, Masako Ikemura, Kenbun Sone, Mayuyo Mori‐Uchino, Hiroko Matsunaga, Tetsushi Tsuruga, Takeshi Nagamatsu, Iwao Kukimoto, Osamu Wada‐Hiraike, Masahito Kawazu, Tetsuo Ushiku, Haruko Takeyama, Katsutoshi Oda, Kei Kawana, Yoshitaka Hippo, and Yutaka Osuga
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging - Published
- 2023
6. Impact of the COVID‐19 pandemic on pathological autopsy practices in Japan
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Yuichiro Hirata, Shun Iida, Takeshi Arashiro, Sayaka Nagasawa, Hisako Saitoh, Hiroyuki Abe, Masako Ikemura, Yohsuke Makino, Rintaro Sawa, Hirotaro Iwase, Tetsuo Ushiku, Tadaki Suzuki, and Shinji Akitomi
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General Medicine ,Pathology and Forensic Medicine - Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, autopsies have provided valuable insights into the pathogenesis of COVID-19. The precise effect of this pandemic on autopsy procedures in Japan, especially in instances unrelated to COVID-19, has not yet been established. Therefore, we conducted a questionnaire survey from December 2020 to January 2021 regarding the status of pathological autopsy practices in Japan during the first year of the COVID-19 pandemic. The questionnaire was sent to 678 medical facilities with pathologists, of which 227 responded. In cases where a confirmed diagnosis of COVID-19 was not made at the time of autopsy, many facilities counted them as suspected COVID-19 cases if pneumonia was suspected clinically. At around half of the sites, autopsies were prohibited for suspected COVID-19 cases. In addition, the number of autopsies of non-COVID-19 cases during the pandemic period was also investigated, and a significant decrease was observed compared with the incidence in the pre-pandemic period. The COVID-19 pandemic has affected not only the autopsies of COVID-19 cases but also the entire practice of pathological autopsies. It is necessary to establish a system that supports the implementation of pathological autopsy practices during the pandemic of an emerging infectious disease.
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- 2023
7. Tie2-Cre–Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury
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Pang-Yen Liu, Nobuaki Fukuma, Yukio Hiroi, Akiko Kunita, Hiroyuki Tokiwa, Kazutaka Ueda, Taro Kariya, Genri Numata, Yusuke Adachi, Miyu Tajima, Masayuki Toyoda, Yuxin Li, Kensuke Noma, Mutsuo Harada, Haruhiro Toko, Tetsuo Ushiku, Yoshimitsu Kanai, Eiki Takimoto, James K. Liao, and Issei Komuro
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Cardiology and Cardiovascular Medicine - Published
- 2023
8. Derivation of pancreatic acinar cell carcinoma cell line <scp>HS</scp> ‐1 as a patient‐derived tumor organoid
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Daisuke Hoshi, Emiri Kita, Yoshiaki Maru, Hiroyuki Kogashi, Yuki Nakamura, Yasutoshi Tatsumi, Osamu Shimozato, Kazuyoshi Nakamura, Kentaro Sudo, Akiko Tsujimoto, Ryo Yokoyama, Atsushi Kato, Tetsuo Ushiku, Masashi Fukayama, Makiko Itami, Taketo Yamaguchi, and Yoshitaka Hippo
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Cancer Research ,Oncology ,General Medicine - Abstract
Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future.
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- 2022
9. Atypical Neurofibromatous Neoplasm with Uncertain Biologic Potential in the Posterior Mediastinum of a Young Patient with Neurofibromatosis Type 1: A Case Report
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Kodai Miyamoto, Hiroshi Kobayashi, Liuzhe Zhang, Yusuke Tsuda, Naohiro Makise, Yoichi Yasunaga, Masako Ikemura, Yudai Nakai, Eisuke Shibata, Tetsuo Ushiku, and Sakae Tanaka
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Oncology - Abstract
Atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP), proposed in a recent NIH consensus overview, is a rare precursor entity of malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) patients. Only one report on imaging findings of ANNUBP is available. Herein, we present the case of a 19-year-old female, diagnosed with a mediastinal tumor by chance, who visited to our hospital. She had café-au-lait spots on her trunk and a past history of resected neurofibroma. Her family also had café-au-lait spots; therefore, an NF1-induced tumor was strongly suspected. MRI revealed a paravertebral mass of 7.5 cm in size consisting of an inner rim with low T2 signal intensity and an outer rim with high T2 intensity, which was similar to a target sign, adjacent to the pulmonary veins; the center of the tumor was well enhanced by gadolinium, and the peripheral region was myxoid and slightly enhanced. FDG-PET showed high FDG uptake, SUVmax of 8.5, although the peripheral region represented low FDG accumulation. CT-guided needle biopsy was repeated because of the suspicion of an MPNST, which resulted in the histopathological diagnosis of ANNUBP. Marginal tumor resection was performed, and the final post-resection histopathological diagnosis was ANNUBP transformed from neurofibroma; the region of ANNUBP lost p16 immunostaining, although it was retained in the peripheral region of the neurofibroma. There has been no recurrence or metastasis 1 year after treatment. In conclusion, ANNUBP could be represented as a well-enhanced homogeneous mass on MRI and a high FDG accumulated region on FDG PET/CT, as seen in MPNST, in NF1 patients.
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- 2022
10. Insulinoma-associated-1 (INSM1) expression in thymic squamous cell carcinoma
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Jumpei Kashima, Taiki Hashimoto, Akihiko Yoshida, Yasushi Goto, Tetsuo Ushiku, Yuichiro Ohe, Shun-ichi Watanabe, and Yasushi Yatabe
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Cell Biology ,General Medicine ,Molecular Biology ,Pathology and Forensic Medicine - Abstract
Thymic squamous cell carcinoma (TSC) presents distinct immunohistochemical features with its expression of CD5 and CD117, both of which are rarely expressed in squamous cell carcinoma in other organs. We found insulinoma-associated-1 (INSM1) expression in some TSCs; thus, a series of thymic tumors were examined retrospectively. Using surgically resected thymic tumors (TSC, n = 35; thymic atypical carcinoid [TAC], n = 4; and thymoma, n = 112) and non-neoplastic thymic tissue (n = 26), we evaluated immunohistochemically the expressions of INSM1, ASCL1, SOX2, NE markers (synaptophysin, chromogranin A, and CD56), and conventional TSC markers (CD5 and CD117). INSM1 was expressed in 22 TSCs (63%), whereas the positive frequencies of synaptophysin, chromogranin A, and CD56 were limited to 13, 10, and 1 cases, respectively. The discordance was highly contrasted with concordantly positive TACs. INSM1 and NE makers were rarely expressed in thymomas. INSM1 expression in TSCs was also associated with CD5 expression, which was significantly less frequent in INSM1-negative TSCs. INSM1, ASCL1, and SOX2 expressions were correlated with one another, but none of the single transcription factors or their combinations is associated with NE expression. The non-neoplastic medullary thymic epithelium was dispersedly positive for INSM1, particularly around Hassall's corpuscles. Despite positive INSM1, a significant decrease in the frequency of NE maker expression may present as a diagnostic pitfall in TSCs. Furthermore, the discordance, which was inherent in the non-neoplastic thymic epithelium, might be a characteristic feature in TSCs.
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- 2022
11. Loss of <scp>H3K27</scp> trimethylation in a distinct group of de‐differentiated chordoma of the skull base
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Naohiro Makise, Tatsunori Shimoi, Kuniko Sunami, Yasuko Aoyagi, Hiroshi Kobayashi, Shota Tanaka, Akira Kawai, Kan Yonemori, Tetsuo Ushiku, and Akihiko Yoshida
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Histology ,General Medicine ,Pathology and Forensic Medicine - Abstract
De-differentiated chordoma is defined as a high-grade sarcoma lacking notochordal differentiation, which arises in association with conventional chordoma. The mechanism underlying de-differentiation remains unclear. We immunohistochemically investigated trimethylation at lysine 27 of histone 3 (H3K27me3) in nine de-differentiated chordomas. The tumours occurred at the skull base (n = 5) or the sacrum (n = 4) in four men and five women with a median age of 50 years. De-differentiation occurred de novo in four cases and at recurrence/metastasis in five cases. Five tumours retained H3K27me3, whereas four showed complete loss of H3K27me3 only in the de-differentiated component, while the conventional chordoma component retained H3K27me3. All the H3K27me3-negative tumours showed co-loss of dimethylation at H3K27 (H3K27me2), consistent with inactivation of polycomb repressive complex 2. Two genetically analysed H3K27me3-negative tumours harboured EED homozygous deletions. All four H3K27me3-negative de-differentiated chordomas affected the skull base of young or middle-aged women. Unlike dense proliferation of highly pleomorphic spindle or epithelioid cells in the H3K27me3-positive de-differentiated chordomas, all H3K27me3-negative tumours displayed swirling fascicles of relatively uniform spindle cells with alternating cellularity and perivascular accentuation, resembling malignant peripheral nerve sheath tumour (MPNST). Rhabdomyoblastic differentiation was present in one H3K27me3-negative tumour. We identified a novel group of de-differentiated chordomas in the skull base that lost H3K27me3/me2 only in the de-differentiated component, which was associated with EED homozygous deletion and MPNST-like histology. Our data suggest a distinct 'polycomb-type' de-differentiation pathway in chordoma, similar to a recently described de-differentiated chondrosarcoma with H3K27me3 loss.
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- 2022
12. Clinical practice guidelines for duodenal cancer 2021
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Kenji Nakagawa, Masayuki Sho, Mitsuhiro Fujishiro, Naomi Kakushima, Takahiro Horimatsu, Ken-ichi Okada, Mikitaka Iguchi, Toshio Uraoka, Motohiko Kato, Yorimasa Yamamoto, Toru Aoyama, Takahiro Akahori, Hidetoshi Eguchi, Shingo Kanaji, Kengo Kanetaka, Shinji Kuroda, Yuichi Nagakawa, Souya Nunobe, Ryota Higuchi, Tsutomu Fujii, Hiroharu Yamashita, Suguru Yamada, Yukiya Narita, Yoshitaka Honma, Kei Muro, Tetsuo Ushiku, Yasuo Ejima, Hiroki Yamaue, and Yasuhiro Kodera
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Gastroenterology - Abstract
Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).
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- 2022
13. Nucleic acid–triggered tumoral immunity propagates <scp>pH</scp> ‐selective therapeutic antibodies through tumor‐driven epitope spreading
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Genta Furuya, Hiroto Katoh, Shinichiro Atsumi, Itaru Hashimoto, Daisuke Komura, Ryo Hatanaka, Shogo Senga, Shuto Hayashi, Shoji Akita, Hirofumi Matsumura, Akihiro Miura, Hideaki Mita, Makoto Nakakido, Satoru Nagatoishi, Akira Sugiyama, Ryohei Suzuki, Hiroki Konishi, Asami Yamamoto, Hiroyuki Abe, Nobuyoshi Hiraoka, Kazunori Aoki, Yasumasa Kato, Yasuyuki Seto, Chihoko Yoshimura, Kazutaka Miyadera, Kouhei Tsumoto, Tetsuo Ushiku, and Shumpei Ishikawa
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Epitopes ,Cancer Research ,Oncology ,Nucleic Acids ,Neoplasms ,Antigens, Surface ,Humans ,General Medicine ,Antigens ,Hydrogen-Ion Concentration ,Antibodies - Abstract
Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.
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- 2022
14. Adenocarcinoma of the stomach and esophagogastric junction with low DNA methylation show poor prognoses
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Masayuki Urabe, Keisuke Matsusaka, Tetsuo Ushiku, Masaki Fukuyo, Bahityar Rahmutulla, Hiroharu Yamashita, Yasuyuki Seto, Masashi Fukayama, and Atsushi Kaneda
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Cancer Research ,Oncology ,Gastroenterology ,General Medicine - Abstract
Gastric cancer (GC) is characterized by unique DNA methylation epigenotypes (MEs). However, MEs including adenocarcinomas of the esophagogastric junction (AEG) and background non-neoplastic columnar mucosae (NM) remain to be clarified.We analyzed the genome-wide DNA MEs of AEG, GC, and background NM using the Infinium 450 k beadarray, followed by quantitative pyrosequencing validation. Large-scale data from The Cancer Genome Atlas (TCGA) were also reviewed.Unsupervised two-way hierarchical clustering using Infinium data of 21 AEG, 30 GC, and 11 NM revealed four DNA MEs: extremely high-ME (E-HME), high-ME (HME), low-ME (LME), and extremely low-ME (E-LME). Promoter methylation levels were validated by pyrosequencing in 146 samples. Non-inflammatory normal mucosae were clustered into E-LME, whereas gastric or esophagogastric junction mucosae with chronic inflammatory changes caused by either Helicobacter pylori infection or reflux esophagitis were clustered together into LME, suggesting that inflammation status determined DNA MEs regardless of the cause. Three cases of Barrett's-related adenocarcinoma were clustered into HME. Among 94 patients whose tumors could be clustered into one of four MEs, 11 patients with E-LME cancers showed significantly shorter overall survival than that in the other MEs, even with the multivariate Cox regression estimate. TCGA data also showed enrichment of AEG in HME and a poorer prognosis in E-LME.E-LME cases, newly confirmed in this study, form a unique subtype with poor prognosis that is not associated with inflammation-associated elevation of DNA methylation levels. LME could be acquired via chronic inflammation, regardless of the cause, and AEG might preferentially show HME.
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- 2022
15. Transcriptome analysis reveals the essential role of NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) in gastric adenocarcinoma of fundic-gland type
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Kazushi Fukagawa, Yu Takahashi, Nobutake Yamamichi, Natsuko Kageyama-Yahara, Yoshiki Sakaguchi, Miho Obata, Rina Cho, Nobuyuki Sakuma, Sayaka Nagao, Yuko Miura, Naoki Tamura, Daisuke Ohki, Hiroya Mizutani, Seiichi Yakabi, Chihiro Minatsuki, Keiko Niimi, Yosuke Tsuji, Mitsue Yamamichi, Narumi Shigi, Shuta Tomida, Hiroyuki Abe, Tetsuo Ushiku, Kazuhiko Koike, and Mitsuhiro Fujishiro
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Cancer Research ,Oncology ,Gastroenterology ,General Medicine - Abstract
Gastric adenocarcinoma of fundic-gland type (GA-FG) is a gastric malignancy with little relation to Helicobacter pylori. Clinical characteristics of GA-FG have been established, but molecular mechanisms leading to tumorigenesis have not yet been elucidated.We subjected three GA-FG tumors-normal mucosa pairs to microarray analysis. Network analysis was performed for the top 30 up-regulated gene transcripts, followed by immunohistochemical staining to confirm the gene expression analysis results. AGS and NUGC4 cells were transfected with the gene-encoding NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) to evaluate transcriptional changes in its target genes.Comprehensive gene expression analysis identified 1410 up-regulated and 1395 down-regulated gene probes with ≥ two-fold difference in expression. Among the top 30 up-regulated genes in GA-FG, we identified transcription factor NKX2-1/TTF-1, a master regulator of lung/thyroid differentiation, together with surfactant protein B (SFTPB), SFTPC, and secretoglobin family 3A member 2(SCGB3A2), which are regulated by NKX2-1/TTF-1. Immunohistochemical analysis of 16 GA-FG specimens demonstrated significantly higher NKX2-1/TTF-1 and SFTPB levels, as compared to that in adjacent normal mucosa (P 0.05), while SCGB3A2 levels did not differ (P = 0.341). Transduction of NKX2-1/TTF-1 into AGS and NUGC4 cells induced transactivation of SFTPB and SFTPC, indicating that NKX2-1/TTF-1 can function as normally in gastric cells as it can in the lung cells.Our first transcriptome analysis of GA-FG indicates significant expression of NKX2-1/TTF1 in GA-FG. Immunohistochemistry and cell biology show ectopic expression and normal transactivation ability of NKX2-1/TTF-1, suggesting that it plays an essential role in GA-FG development.
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- 2022
16. Clinical usefulness of a novel classification of T cell distribution patterns in the tumor microenvironment of follicular lymphoma to detect transformation
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Hirotaka Miyashita, Kazuki Taoka, Ayako Kume, Aya Ushiku, Tetsuo Ushiku, Kazuhiro Toyama, and Mineo Kurokawa
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Cohort Studies ,T-Lymphocytes ,Tumor Microenvironment ,Humans ,Hematology ,General Medicine ,Prognosis ,Lymphoma, Follicular ,Retrospective Studies - Abstract
The clinical course of follicular lymphoma (FL) is thought to be influenced by the infiltrating immune cells in the tumor microenvironment. Focusing on the distribution patterns of T cells may be a promising approach to estimate the prognosis of FL, especially histological transformation. This study was a retrospectively cohort study in the relationship between the pathological distribution pattern of T cells in the tumor microenvironment and clinical course of FL. One hundred twenty-eight patients with FL initially diagnosed at the University of Tokyo Hospital from January 2008 to January 2017 were evaluated. We classified each patient's specimen at initial diagnosis by the distribution pattern of tumor infiltrating CD3-positive cells, intra-follicle focal (IFF), intra-follicle diffuse (IFD), extra-follicle marginal (EFM), and extra-follicle diffuse (EFD). We analyzed the distribution pattern's correlation with other prognostic factors including overall survival (OS), progression free survival (PFS), and transformation. Among 128 cases, 81 had evaluable pathological specimen. Based on our criteria, in the intra-follicle,17 cases (21%) were classified as IFF. Sixty-four cases (79%) were classified as IFD. In the extra follicle, 25 cases (31%) were classified as EFM. Fifty-six cases (69%) were classified as EFD. There was significant difference in risk of transformation between the EFM and EFD around extra-follicle area in the adjusted model (p 0.05). Also, cases with IFF and EFM had significantly higher risk of transformation compared to cases with other T cell distribution patterns (p 0.01). We proposed a new classification of CD3-positive T cell distribution patterns around the follicle lesions in FL and demonstrated its clinical significance.
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- 2022
17. Dramatic response to entrectinib in a patient with malignant peripheral nerve sheath tumor harboring novel SNRNP70‐NTRK3 fusion gene
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Hiroshi Kobayashi, Naohiro Makise, Aya Shinozaki‐Ushiku, Liuzhe Zhang, Yuki Ishibashi, Masachika Ikegami, Yusuke Tsuda, Shinji Kohsaka, Tetsuo Ushiku, Katsutoshi Oda, Kiyoshi Miyagawa, Hiroyuki Aburatani, Hiroyuki Mano, and Sakae Tanaka
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Male ,Cancer Research ,Neurofibrosarcoma ,Biomarkers, Tumor ,Genetics ,Humans ,RNA ,Middle Aged ,Immunohistochemistry ,Ribonucleoprotein, U1 Small Nuclear - Abstract
Neurotropic tropomyosin receptor kinase (NTRK) gene rearrangements have been reported in limited cases of sarcomas; however, to date, there has been only one report of such rearrangements in malignant peripheral nerve sheath tumors (MPNSTs). Herein, we describe a 51-year-old male patient with a buttock tumor arising from the sciatic nerve, which was diagnosed as MPNST with positive S-100 staining, negative SOX10 staining, and loss of trimethylation at lysine 27 of histone H3 (H3K27me3) confirmed by immunohistochemistry. Soon after the resection of the primary tumor, the patient was found to have pulmonary and lymph node metastases. Chemotherapy with eribulin and trabectedin showed limited effects. However, the patient responded rapidly to pazopanib, but severe side effects caused discontinuation of the treatment. RNA panel testing revealed a novel fusion gene between Small Nuclear Ribonucleoprotein U1 Subunit 70 (SNRNP70) gene and NTRK3 gene. Furthermore, loss of NF1, SUZ12, and CDKN2A genes was confirmed by DNA panel testing, which is compatible with a histological diagnosis of MPNST. SNRNP70 possesses a coiled-coiled domain and seems to induce constitutive activation of NTRK3 through dimerization. In fact, immunohistochemistry revealed diffuse staining of pan-TRK within tumor cells. Treatment with entrectinib, which is an NTRK inhibitor, showed a quick and durable response for 10 months. Although NTRK rearrangements are very rare in MPNST, this case highlights the importance of genetic testing in MPNST, especially using an RNA panel for the detection of rare fusion genes.
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- 2022
18. Development and multi‐institutional validation of an artificial intelligence‐based diagnostic system for gastric biopsy
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Hiroyuki, Abe, Yusuke, Kurose, Shusuke, Takahama, Ayako, Kume, Shu, Nishida, Miyako, Fukasawa, Yoichi, Yasunaga, Tetsuo, Ushiku, Youichiro, Ninomiya, Akihiko, Yoshizawa, Kohei, Murao, Shin'ichi, Sato, Masaru, Kitsuregawa, Tatsuya, Harada, Masanobu, Kitagawa, and Masashi, Fukayama
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Cancer Research ,Oncology ,Artificial Intelligence ,Biopsy ,Stomach ,Humans ,General Medicine - Abstract
To overcome the increasing burden on pathologists in diagnosing gastric biopsies, we developed an artificial intelligence-based system for the pathological diagnosis of gastric biopsies (AI-G), which is expected to work well in daily clinical practice in multiple institutes. The multistage semantic segmentation for pathology (MSP) method utilizes the distribution of feature values extracted from patches of whole-slide images (WSI) like pathologists' "low-power view" information of microscopy. The training dataset included WSIs of 4511 gastric biopsy tissues from 984 patients. In tissue-level validation, MSP AI-G showed better accuracy (91.0%) than that of conventional patch-based AI-G (PB AI-G) (89.8%). Importantly, MSP AI-G unanimously achieved higher accuracy rates (0.946 ± 0.023) than PB AI-G (0.861 ± 0.078) in tissue-level analysis, when applied to the cohorts of 10 different institutes (3450 samples of 1772 patients in all institutes, 198-555 samples of 143-206 patients in each institute). MSP AI-G had high diagnostic accuracy and robustness in multi-institutions. When pathologists selectively review specimens in which pathologist's diagnosis and AI prediction are discordant, the requirement of a secondary review process is significantly less compared with reviewing all specimens by another pathologist.
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- 2022
19. Essence of postmortem computed tomography for in-hospital deaths: what clinical radiologists should know
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Masanori Ishida, Wataru Gonoi, Hiroyuki Abe, Tetsuo Ushiku, and Osamu Abe
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Radiology, Nuclear Medicine and imaging - Abstract
Postmortem computed tomography (CT) is an essential tool for investigating the causes of death. Postmortem CT has characteristic imaging findings and should not be interpreted in the same manner as clinical antemortem images. In analyzing the cause of death in in-hospital death cases using postmortem images, it is crucial to understand early postmortem and post-resuscitation changes. In addition, it is essential to understand the limitations of diagnosing the cause of death or significant pathology relating to death on non-contrast-enhanced postmortem CT. In Japan, there has also been social demand to establish a system for postmortem imaging at the time of death. To facilitate such a system, clinical radiologists should be prepared to interpret postmortem images and assess the cause of death. This review article provides comprehensive information regarding unenhanced postmortem CT for in-hospital death cases in daily clinical practice in Japan.
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- 2023
20. Human resources for administrative work to carry out a comprehensive genomic profiling test in Japan
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Hidenori Kage, Katsutoshi Oda, Manabu Muto, Katsuya Tsuchihara, Natsuko Okita, Yusuke Okuma, Junko Kikuchi, Hidekazu Shirota, Hideyuki Hayashi, Toshio Kokuryo, Daisuke Sakai, Akira Hirasawa, Makoto Kubo, Hirotsugu Kenmotsu, Nana Akiyama, Aya Shinozaki‐Ushiku, Masahiko Tanabe, Tetsuo Ushiku, Kiyoshi Miyagawa, and Yasuyuki Seto
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Cancer Research ,Oncology ,General Medicine - Published
- 2023
21. KRAS mutation in intrahepatic cholangiocarcinoma: Linkage with metastasis‐free survival and reduced E‐cadherin expression
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Mariko Tanaka, Akiko Kunita, Makoto Yamagishi, Hiroto Katoh, Shumpei Ishikawa, Hiroyuki Yamamoto, Jun Abe, Junichi Arita, Kiyoshi Hasegawa, Tatsuhiro Shibata, and Tetsuo Ushiku
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Cholangiocarcinoma ,Proto-Oncogene Proteins p21(ras) ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Hepatology ,Antigens, CD ,Mutation ,Humans ,Interferons ,Cadherins ,Prognosis ,Disease-Free Survival - Abstract
Although KRAS mutations are the major driver of intrahepatic cholangiocarcinoma (ICC), their role remains unexplored. This study aimed to elucidate the prognostic effects, association with clinicopathologic characteristics and potent functions of KRAS mutations in ICC.A hundred and seven resected stage I-III ICCs were analysed for KRAS mutation status and its link with clinicopathological features. An independent validation cohort (n = 138) was included. In vitro analyses using KRAS-mutant ICC cell lines were performed.KRAS mutation was significantly associated with worse overall survival in stage I-III ICCs, which was validated in an independent cohort. Recurrence-free survival did not significantly differ between cases with and without KRAS mutations, but if limited to recurrence with extrahepatic metastasis, KRAS-mutant cases showed significantly worse distant metastasis-free survival than KRAS-wild cases showed. KRAS mutations were associated with frequent tumour budding with reduced E-cadherin expression. In vitro, KRAS depletion caused marked inhibition of cell growth and migration together with E-cadherin upregulation in KRAS-mutant ICC cells. The RNA-sequencing assay revealed that KRAS depletion caused MYC pathway downregulation and interferon pathway upregulation.Our observations suggest that KRAS mutations are associated with aggressive behaviour of ICC, especially the development of extrahepatic metastasis. Mutant KRAS is likely to change the adhesive status of ICC cells, affect the responsiveness of tumour cells to interferon immune signals, and consequently promote extrahepatic metastasis. KRAS mutation status, which predicts the prognoses of patients with ICC after surgical resection, is expected to help stratify patients better for individual postoperative treatment strategies.
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- 2022
22. High‐grade transformation of pancreatic neuroendocrine tumor associated with TP53 mutations: A diagnostic pitfall mimicking neuroendocrine carcinoma
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Mariko Tanaka, Aya Shinozaki‐Ushiku, Akiko Kunita, Yoichi Yasunaga, Nobuhisa Akamatsu, Kiyoshi Hasegawa, and Tetsuo Ushiku
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General Medicine ,Pathology and Forensic Medicine - Published
- 2022
23. KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer
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Tatsunori, Suzuki, Yohei, Masugi, Yosuke, Inoue, Tsuyoshi, Hamada, Mariko, Tanaka, Manabu, Takamatsu, Junichi, Arita, Tomotaka, Kato, Yoshikuni, Kawaguchi, Akiko, Kunita, Yousuke, Nakai, Yutaka, Nakano, Yoshihiro, Ono, Naoki, Sasahira, Tsuyoshi, Takeda, Keisuke, Tateishi, Sho, Uemura, Kazuhiko, Koike, Tetsuo, Ushiku, Kengo, Takeuchi, Michiie, Sakamoto, Kiyoshi, Hasegawa, Minoru, Kitago, Yu, Takahashi, and Mitsuhiro, Fujishiro
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Pancreatic Neoplasms ,Proto-Oncogene Proteins p21(ras) ,Cancer Research ,Gene Frequency ,Oncology ,Mutation ,Biomarkers, Tumor ,Humans ,General Medicine ,Prognosis - Abstract
KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; p
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- 2022
24. Enhanced PD-L1 Expression in LMP1-positive Cells of Epstein-Barr Virus–associated Malignant Lymphomas and Lymphoproliferative Disorders
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Ayako Kume, Aya Shinozaki-Ushiku, Akiko Kunita, Atsushi Kondo, and Tetsuo Ushiku
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Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Ligands ,Immunohistochemistry ,B7-H1 Antigen ,Lymphoproliferative Disorders ,Pathology and Forensic Medicine ,Lymphoma, Extranodal NK-T-Cell ,Viral Proteins ,Epstein-Barr Virus Nuclear Antigens ,Humans ,Surgery ,Anatomy ,Immune Checkpoint Inhibitors ,Biomarkers ,In Situ Hybridization - Abstract
Epstein-Barr virus (EBV) is associated with various types of human malignancies and with programmed death ligand (PD-L) 1 expression in neoplastic cells. However, in EBV-associated malignant lymphomas and lymphoproliferative disorders (LPDs), there is limited information regarding PD-L1 expression profiles among different histologic types and patterns of EBV latency. First, we investigated PD-L1 and EBV latent gene expression using conventional immunohistochemistry and in situ hybridization in 42 EBV-associated malignant lymphomas and LPDs. Classic Hodgkin lymphoma showed the highest PD-L1 expression with diffuse expression in all cases, followed by diffuse large B-cell lymphoma/Burkitt lymphoma, LPDs, and extranodal NK/T-cell lymphoma. EBV latency at the case level was not associated with PD-L1 expression. We further evaluated the expression of PD-L1 and EBV latent genes in tumor cells at single-cell resolution using multiplex fluorescence imaging. This analysis revealed that positivity rates of latent membrane protein (LMP) 1 in tumor cells were 1.0% to 89.5% (mean 35.4%) in latency type II/III cases, and LMP1 + cells showed more frequent PD-L1 expression than LMP1 - cells ( Plt;0.0001, paired t test). In contrast, no association was observed between EBV nuclear antigen 2 and PD-L1 expression. Notably, tumor cells exhibiting Hodgkin/Reed-Sternberg cell-like morphology co-expressed PD-L1 and LMP1 more often than those that do not. Our observations suggested that LMP1 upregulates PD-L1 expression and is a potential biomarker for predicting the efficacy of immune checkpoint inhibitors. In addition, the heterogeneous expression of PD-L1 and EBV latent genes may produce diverse tumor cells with different oncogenic and immune-evasive properties, leading to resistance to targeted therapies.
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- 2022
25. Machine learning–based personalized prediction of gastric cancer incidence using the endoscopic and histologic findings at the initial endoscopy
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Junya Arai, Tomonori Aoki, Masaya Sato, Ryota Niikura, Nobumi Suzuki, Rei Ishibashi, Yosuke Tsuji, Atsuo Yamada, Yoshihiro Hirata, Tetsuo Ushiku, Yoku Hayakawa, and Mitsuhiro Fujishiro
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Gastritis, Atrophic ,Metaplasia ,Helicobacter pylori ,Incidence ,Gastroenterology ,Endoscopy, Gastrointestinal ,Helicobacter Infections ,Machine Learning ,Gastric Mucosa ,Risk Factors ,Stomach Neoplasms ,Gastritis ,Humans ,Radiology, Nuclear Medicine and imaging ,Atrophy ,Retrospective Studies - Abstract
Accurate risk stratification for gastric cancer is required for optimal endoscopic surveillance in patients with chronic gastritis. We aimed to develop a machine learning (ML) model that incorporates endoscopic and histologic findings for an individualized prediction of gastric cancer incidence.We retrospectively evaluated 1099 patients with chronic gastritis who underwent EGD and biopsy sampling of the gastric mucosa. Patients were randomly divided into training and test sets (4:1). We constructed a conventional Cox proportional hazard model and 3 ML models. Baseline characteristics, endoscopic atrophy, and Operative Link on Gastritis-Intestinal Metaplasia Assessment (OLGIM)/Operative Link on Gastritis Assessment (OLGA) stage at initial EGD were comprehensively assessed. Model performance was evaluated using Harrel's c-index.During a mean follow-up of 5.63 years, 94 patients (8.55%) developed gastric cancer. The gradient-boosting decision tree (GBDT) model achieved the best performance (c-index from the test set, .84) and showed high discriminative ability in stratifying the test set into 3 risk categories (P .001). Age, OLGIM/OLGA stage, endoscopic atrophy, and history of malignant tumors other than gastric cancer were important predictors of gastric cancer incidence in the GBDT model. Furthermore, the proposed GBDT model enabled the generation of a personalized cumulative incidence prediction curve for each patient.We developed a novel ML model that incorporates endoscopic and histologic findings at initial EGD for personalized risk prediction of gastric cancer. This model may lead to the development of effective and personalized follow-up strategies after initial EGD.
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- 2022
26. Histological growth patterns of colorectal cancer liver metastases: a strong prognostic marker associated with invasive patterns of the primary tumor and p53 alteration
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Hiroyuki Abe, Yoichi Yasunaga, Sho Yamazawa, Yudai Nakai, Wataru Gonoi, Yujiro Nishioka, Koji Murono, Kazuhito Sasaki, Junichi Arita, Kazushige Kawai, Hiroaki Nozawa, Kiyoshi Hasegawa, Soichiro Ishihara, and Tetsuo Ushiku
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Liver Neoplasms ,Humans ,Tumor Suppressor Protein p53 ,Colorectal Neoplasms ,Prognosis ,Pathology and Forensic Medicine - Abstract
The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P = 0.025), worse recurrence-free survival (P 0.001) and overall survival (P = 0.008). In multivariate analyses, multiple tumors (P 0.001) and non-desmoplastic patterns (P = 0.009) were associated with worse recurrence-free survival, and tumor size (P = 0.025) and non-desmoplastic pattern (P = 0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P = 0.002), high-grade poorly differentiated cluster (P = 0.021), absence of mucinous histology (P = 0.016), and aberrant p53 expression (complete loss or overexpression; P 0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.
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- 2022
27. Neuroendocrine carcinoma associated with chronic ulcerative colitis: a case report and review of the literature
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Yumi Yokota, Hiroyuki Anzai, Yuzo Nagai, Hirofumi Sonoda, Takahide Shinagawa, Yuichiro Yoshioka, Shinya Abe, Yuichiro Yokoyama, Hiroyuki Matsuzaki, Shigenobu Emoto, Koji Murono, Kazuhito Sasaki, Hiroaki Nozawa, Tetsuo Ushiku, and Soichiro Ishihara
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Gastroenterology ,Surgery - Published
- 2023
28. Multimodal imaging findings of intrahepatic cholangiocarcinoma arising from a biliary adenofibroma: a case report with radiological–pathological correlation
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Noriko Kanemaru, Yudai Nakai, Takeyuki Watadani, Takahiro Nakao, Munetoshi Hinata, Akiko Nakazawa, Nobuhisa Akamatsu, Tetsuo Ushiku, Kiyoshi Hasegawa, and Osamu Abe
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Radiological and Ultrasound Technology ,Urology ,Gastroenterology ,Radiology, Nuclear Medicine and imaging - Abstract
Purpose Biliary adenofibroma is a solid microcystic epithelial neoplasm in the liver, comprising microcystic and tubuloacinar glandular tissues lined by a non-mucin secreting biliary epithelium and supported by a fibrous stroma. It is an extremely rare benign tumor with potential for malignant transformation. Herein, we report the case of a 64-year-old woman diagnosed with intrahepatic cholangiocarcinoma arising from biliary adenofibroma. Methods Imaging studies revealed a tumor of 50 mm diameter, consisting of two components in S1 of the liver. The ventral portion of the tumor showed an ill-defined mass with early peripheral and gradual centripetal enhancement invading to the middle hepatic vein on computed tomography (CT), diffusion restriction on magnetic resonance images, and high fluorine-18-2-deoxy-d-glucose (FDG) uptake on positron emission tomography, like conventional intrahepatic cholangiocarcinoma. The dorsal portion showed a well-defined and low-attenuated mass with heterogeneous early enhancement and partial wash-out on CT, marked hyperintensity on heavily T2-weighted images, and low FDG uptake. The patient subsequently underwent extended left hepatectomy. Results Pathologically, the former was diagnosed as cholangiocarcinoma and the latter as biliary adenofibroma. We discuss the radiological-pathological correlation of the tumor with a literature review. Conclusion Preoperative diagnosis of biliary adenofibroma is extremely challenging; however, clinically, it is crucial not to miss the presence of malignant findings. Graphical abstract
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- 2023
29. <scp>PD‐L1</scp> and <scp>HLA</scp> ‐class I expression status and their therapeutic implication in oesophageal small‐cell carcinoma
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Satoshi Yamashita, Hiroyuki Abe, Hiroharu Yamashita, Koichi Yagi, Yasuyuki Seto, and Tetsuo Ushiku
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Histology ,General Medicine ,Pathology and Forensic Medicine - Published
- 2023
30. Real-time fluorescence imaging to identify cholangiocarcinoma in the extrahepatic biliary tree using an enzyme-activatable probe
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Ryugen Takahashi, Takeaki Ishizawa, Yoshinori Inagaki, Mariko Tanaka, Akira Ogasawara, Yugo Kuriki, Kyohhei Fujita, Mako Kamiya, Tetsuo Ushiku, Yasuteru Urano, and Kiyoshi Hasegawa
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Oncology ,Hepatology - Abstract
Introduction Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme. Methods Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues. Results Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of seven patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in four patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA. Discussion/Conclusion Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.
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- 2023
31. Lost expression of AT‐rich interaction domain 1A in the gastric mucosa—A constituent of field cancerization in the stomach
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Hiroyuki Abe, Hirofumi Rokutan, Yasushi Totoki, Hiromi Nakamura, Tatsuhiro Shibata, Tetsuo Ushiku, and Masashi Fukayama
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General Medicine ,Pathology and Forensic Medicine - Published
- 2023
32. Data from Distinct Chemopreventive Effects of Aspirin in Diffuse and Intestinal-Type Gastric Cancer
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Kazuhiko Koike, Masashi Fukayama, Mitsuhiro Fujishiro, Tetsuo Ushiku, Atsuo Yamada, Sozaburo Ihara, Nobumi Suzuki, Mitsuru Konishi, Yoshihiro Hirata, Yoku Hayakawa, and Ryota Niikura
- Abstract
Introduction: Although aspirin/NSAIDs may have potential preventive effects on several cancers, it remains unclear on gastric cancer. The purpose of this study is to compare the risk of developing gastric cancer and the histologic changes of intestinal metaplasia and neutrophil infiltration, between aspirin/NSAID users and nonusers.Methods: Using an electronic endoscopy database in two hospitals from 1996 to 2017, we analyzed the data from patients with chronic gastritis who received aspirin or NSAIDs prior to upper gastrointestinal endoscopy. One-to-one propensity score matching was performed to compare the proportion of gastric cancer, intestinal metaplasia, and neutrophil infiltration between these drug users and nonusers.Results: We analyzed 2,082 aspirin users and 2,082 nonusers as well as 898 NSAID users and 898 nonusers. Six diffuse-type and 19 intestinal-type gastric cancer, 1,243 intestinal metaplasia, and 1,503 neutrophil infiltration patients were identified. The proportion of diffuse-type gastric cancer (0.05%) was 80% lower in aspirin users compared with the nonusers (0.24%), and there was no case of diffuse-type cancer in patients who took aspirin for more than 2 years. In contrast, intestinal-type gastric cancer incidence was significantly higher in aspirin users (0.72%) compared with nonusers (0.14%). No significant differences in the incidence of gastric cancer were found between NSAID use and nonusers. NSAID use was significantly associated with decreased proportion of neutrophil infiltration compared with nonusers.Conclusion: Aspirin may have distinct effects between intestinal-type and diffuse-type gastric cancer development. Cancer Prev Res; 11(5); 279–86. ©2018 AACR.
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- 2023
33. Diverticular perforation of terminal ileum associated with chemotherapy for non-small cell lung carcinoma: a case report
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So Kasuga, Shinya Abe, Hiroaki Nozawa, Kazuhito Sasaki, Koji Murono, Shigenobu Emoto, Hiroyuki Matsuzaki, Yuichiro Yokoyama, Yuzo Nagai, Yuichiro Yoshioka, Takahide Shinagawa, Hirofumi Sonoda, Tetsuo Ushiku, and Soichiro Ishihara
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Surgery - Abstract
A 71-year-old man was diagnosed with advanced non-small cell lung carcinoma and treated with chemotherapy developed ileocecal diverticulitis three times over the last 2 months of receiving second-line treatment. During the fourth diverticulitis event, the patient presented with fever and abdominal pain, worsening after 5 days. Abdominal computed tomography showed ascites and intra-abdominal free air, suggesting bowel perforation with acute diffuse peritonitis. We performed emergency surgery; the surgical findings showed diverticulosis with perforated diverticula in the ileocecal region. We performed ileocecal resection, an ileostomy and a mucous fistula of the ascending colon. Histopathological examinations revealed pseudodiverticula at the perforation, where the mucosa was depressed through the muscularis propria. Hence, we diagnosed perforated ileal diverticulitis. Repeated diverticulitis triggered by chemotherapy might have resulted in perforation. Small bowel diverticula are rare, but diverticulitis can occur in patients receiving chemotherapy and with cases of unexplained fever and abdominal pain.
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- 2023
34. Supplementary Table 1 from Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma
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Masashi Fukayama, Kenzo Takada, Takashi Sakatani, Takeo Nakaya, Teppei Morikawa, Shumpei Ishikawa, Aya Shinozaki, Tetsuo Ushiku, Noriko Murakami, Hiroshi Uozaki, and Rumi Hino
- Abstract
Supplementary Table 1 from Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma
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- 2023
35. Data from Classification of Epstein–Barr Virus–Positive Gastric Cancers by Definition of DNA Methylation Epigenotypes
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Masashi Fukayama, Hiroyuki Aburatani, Kenzo Takada, Yasuyuki Seto, Hiroshi Uozaki, Rumi Hino, Yasuko Kikuchi, Tetsuo Ushiku, Genta Nagae, Atsushi Kaneda, and Keisuke Matsusaka
- Abstract
Epstein–Barr virus (EBV) is associated with Burkitt lymphoma, nasopharyngeal carcinoma, opportunistic lymphomas in immunocompromised hosts, and a fraction of gastric cancers. Aberrant promoter methylation accompanies human gastric carcinogenesis, though the contribution of EBV to such somatic methylation changes has not been fully clarified. We analyzed promoter methylation in gastric cancer cases with Illumina's Infinium BeadArray and used hierarchical clustering analysis to classify gastric cancers into 3 subgroups: EBV−/low methylation, EBV−/high methylation, and EBV+/high methylation. The 3 epigenotypes were characterized by 3 groups of genes: genes methylated specifically in the EBV+ tumors (e.g., CXXC4, TIMP2, and PLXND1), genes methylated both in EBV+ and EBV−/high tumors (e.g., COL9A2, EYA1, and ZNF365), and genes methylated in all of the gastric cancers (e.g., AMPH, SORCS3, and AJAP1). Polycomb repressive complex (PRC) target genes in embryonic stem cells were significantly enriched among EBV−/high-methylation genes and commonly methylated gastric cancer genes (P = 2 × 10−15 and 2 × 10−34, respectively), but not among EBV+ tumor-specific methylation genes (P = 0.2), suggesting a different cause for EBV+-associated de novo methylation. When recombinant EBV was introduced into the EBV−/low-methylation epigenotype gastric cancer cell, MKN7, 3 independently established subclones displayed increases in DNA methylation. The promoters targeted by methylation were mostly shared among the 3 subclones, and the new methylation changes caused gene repression. In summary, DNA methylation profiling classified gastric cancer into 3 epigenotypes, and EBV+ gastric cancers showed distinct methylation patterns likely attributable to EBV infection. Cancer Res; 71(23); 7187–97. ©2011 AACR.
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- 2023
36. Supplementary Methods, Tables 1-5, Figures 1-4 from Classification of Epstein–Barr Virus–Positive Gastric Cancers by Definition of DNA Methylation Epigenotypes
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Masashi Fukayama, Hiroyuki Aburatani, Kenzo Takada, Yasuyuki Seto, Hiroshi Uozaki, Rumi Hino, Yasuko Kikuchi, Tetsuo Ushiku, Genta Nagae, Atsushi Kaneda, and Keisuke Matsusaka
- Abstract
PDF file - 769K
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- 2023
37. Data from Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma
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Masashi Fukayama, Kenzo Takada, Takashi Sakatani, Takeo Nakaya, Teppei Morikawa, Shumpei Ishikawa, Aya Shinozaki, Tetsuo Ushiku, Noriko Murakami, Hiroshi Uozaki, and Rumi Hino
- Abstract
CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV-associated gastric carcinoma (GC). Aberrant promoter methylation and expression loss of PTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohistochemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. PTEN abnormalities were reiterated in GC cell lines MKN-1 and MKN-7 infected with recombinant EBV, and DNA methyltransferase 1 (DNMT1) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-1 similarly showed that viral latent membrane protein 2A (LMP2A) up-regulated DNMT1, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A-mediated DNMT1 overexpression. Immunohistochemistry for both pSTAT3 and DNMT1 showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMP2A induces the phosphorylation of STAT3, which activates DNMT1 transcription and causes PTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer. [Cancer Res 2009;69(7):2766–74]
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- 2023
38. Non-Helicobacter pylori gastric microbiome modulates prooncogenic responses and is associated with gastric cancer risk
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Ryota Niikura, Yoku Hayakawa, Naoyoshi Nagata, Tohru Miyoshi-Akiayama, Koji Miyabayashi, Mayo Tsuboi, Nobumi Suzuki, Masahiro Hata, Junya Arai, Ken Kurokawa, Sohei Abe, Chie Uekura, Kotaro Miyoshi, Sozaburo Ihara, Yoshihiro Hirata, Atsuo Yamada, Hiroaki Fujiwara, Tetsuo Ushiku, Susan L. Woods, Daniel L. Worthley, Masanori Hatakeyama, Yiping W. Han, Timothy C. Wang, Takashi Kawai, and Mitsuhiro Fujishiro
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- 2023
39. SARS-CoV-2 Transmission from Virus-Infected Dead Hamsters
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Kiyoko Iwatsuki-Horimoto, Hiroshi Ueki, Mutsumi Ito, Sayaka Nagasawa, Yuichiro Hirata, Kenichiro Hashizume, Kazuho Ushiwata, Hirotaro Iwase, Yohsuke Makino, Tetsuo Ushiku, Shinji Akitomi, Masaki Imai, Hisako Saitoh, and Yoshihiro Kawaoka
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Molecular Biology ,Microbiology - Abstract
We found that SARS-CoV-2 could be transmitted from a dead body, presumably via postmortem gases. However, we also found that postmortem care, such as plugging the pharynx, nostrils, and rectum or embalming the corpse, could prevent transmission from the dead body. These results indicate that protection from infection is essential when handling infected corpses and that appropriate care of SARS-CoV-2-infected corpses is important.
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- 2023
40. Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct
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Tsuyoshi Hamada, Hiroki Oyama, Yousuke Nakai, Shuichi Tange, Junichi Arita, Ryunosuke Hakuta, Hideaki Ijichi, Kazunaga Ishigaki, Sachiko Kanai, Yoshikuni Kawaguchi, Hirofumi Kogure, Suguru Mizuno, Kei Saito, Tomotaka Saito, Tatsuya Sato, Tatsunori Suzuki, Naminatsu Takahara, Mariko Tanaka, Keisuke Tateishi, Tetsuo Ushiku, Kiyoshi Hasegawa, and Mitsuhiro Fujishiro
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Hepatology ,Gastroenterology - Published
- 2023
41. Overexpression of HIF1α in Hunner Lesions of Interstitial Cystitis: Pathophysiological Implications
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Yoshiyuki Akiyama, Michael A. O’Donnell, Yukio Homma, Tetsuo Ushiku, Yi Luo, Karl J. Kreder, Jimpei Miyakawa, Haruki Kume, and Daichi Maeda
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Pathology ,medicine.medical_specialty ,business.industry ,Protein digestion ,Urology ,Interstitial cystitis ,medicine.disease ,Proinflammatory cytokine ,Lesion ,Biological pathway ,Cytokeratin ,Medicine ,Immunohistochemistry ,Tumor necrosis factor alpha ,medicine.symptom ,business - Abstract
Purpose To elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles. Materials and methods Paired bladder mucosal biopsies, one sample each from the Hunner lesion and non-lesion area, were obtained from 25 patients with Hunner-type interstitial cystitis. The samples were subjected to whole-transcriptome profiling; immunohistochemical quantification of CD3, CD4, CD8, CD20, CD138, mast cell tryptase, cytokeratin, and HIF1α; and quantitative polymerase chain reaction for IFN-α, IFN-β, IFN-γ, TNF, TGF-β1, HIF1α, IL-2, IL-4, IL-6, IL-10, and IL-12A. The results were compared between the lesion and non-lesion areas. Results RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (N=24) included "HIF1α signaling pathway", "PI3K-Akt signaling pathway", "RAS signaling pathway", and "MAPK signaling pathway." By contrast, down-regulated pathways (N=6) included "basal cell carcinoma" and "protein digestion and absorption". The mRNA levels of HIF1α, IFN-γ, and IL-2 and the HIF1α protein level were significantly higher in lesion areas. Otherwise, there were no significant differences between the lesion and non-lesion samples in terms of mRNA levels of inflammatory cytokines or histological features such as lymphoplasmacytic and mast cell infiltration, epithelial denudation, and CD4/CD8 T-lymphocyte ratio. Conclusions Our findings demonstrate significant overexpression of HIF1α and up-regulation of its related biological pathways in Hunner lesions. The results indicate that ischemia, in conjunction with inflammation, plays a pathophysiological role in this subtype of interstitial cystitis/bladder pain syndrome, particularly in Hunner lesions.
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- 2022
42. Impact of the viability assessment of lateral lymph node metastasis in rectal cancer after neoadjuvant chemoradiotherapy
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Kosuke Ozaki, Kazushige Kawai, Hiroaki Nozawa, Kazuhito Sasaki, Koji Murono, Shigenobu Emoto, Hiroyuki Abe, Tetsuo Ushiku, and Soichiro Ishihara
- Subjects
Rectal Neoplasms ,Lymphatic Metastasis ,Gastroenterology ,Humans ,Lymph Node Excision ,Chemoradiotherapy ,Lymph Nodes ,Neoplasm Recurrence, Local ,Neoadjuvant Therapy ,Neoplasm Staging ,Retrospective Studies - Abstract
Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) without lateral lymph node (LLN) dissection is widely performed for lower advanced rectal cancer. However, it is unclear whether residual cancer cells in the LLNs undergo apoptosis, disappear, or regrow if unresected.Overall, 293 consecutive patients with T3/4 rectal cancer who underwent CRT followed by radical surgery between September 2003 and December 2018 were retrospectively reviewed. We assessed apoptosis of the residual primary tumor, mesorectum lymph nodes (MLN), and LLN using M30 cytoDEATH immunostaining and evaluated the degree of apoptosis. The difference in the prognosis of the lateral lymph node metastasis positive (LLNM +) and lateral lymph node metastasis negative (LLNM-) groups was assessed.There were 31 patients (10.6%) who were diagnosed with a complete response by hematoxylin and eosin (HE) staining. The residual cancer cells showed complete apoptosis in the primary lesion in 28 patients, in the metastatic MLN in only two patients, and in the metastatic LLN in one patient. The LLNM + group had a significantly poorer distant recurrence, recurrence-free survival, and overall survival than the LLNM- group.The majority of the residual cancer tissue in LNs observed by HE staining was found to be non-apoptotic. If LLN metastasis is suspected on pretreatment imaging, performing LLN dissection together with TME should be considered.
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- 2022
43. A Case of Resected Mixed Acinar-neuroendocrine Carcinoma with Synchronous Liver Metastases
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Yoshikuni KAWAGUCHI, Yuhi YOSHIZAKI, Mariko TANAKA, Junichi ARITA, Tetsuo USHIKU, and Kiyoshi HASEGAWA
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General Engineering ,General Earth and Planetary Sciences ,General Environmental Science - Published
- 2022
44. Impact of a Novel Digital Therapeutics System on Nonalcoholic Steatohepatitis: The NASH App Clinical Trial
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Masaya Sato, Masatoshi Akamatsu, Toshihide Shima, Tadashi Ikegami, Mikio Yanase, Shintaro Mikami, Jun Imamura, Takuma Nakatsuka, Ryosuke Tateishi, Naoko Yamauchi, Tetsuo Ushiku, Takeshi Okanoue, Mitsuhiro Fujishiro, Eisuke Hida, and Kazuhiko Koike
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Hepatology ,Gastroenterology - Published
- 2023
45. Increased expression of TNFRSF14 and LIGHT in biliary epithelial cells of patients with primary sclerosing cholangitis
- Author
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Sachiko Kanai, Hiroaki Fujiwara, Suguru Mizuno, Takahiro Kishikawa, Takuma Nakatsuka, Tsuyoshi Hamada, Mariko Tanaka, Junichi Arita, Yousuke Nakai, Hiroyuki Isayama, Masato Kasuga, Ryosuke Tateishi, Keisuke Tateishi, Tetsuo Ushiku, Kiyoshi Hasegawa, Kazuhiko Koike, and Mitsuhiro Fujishiro
- Abstract
Background and aims: There is a lack of biliary epithelial molecular markers for primary sclerosing cholangitis (PSC). We analyzed candidates from disease susceptibility genes identified in recent genome-wide association studies. Methods: Expression was quantified using immunohistochemistry in biliary epithelia in liver biopsy samples from patients with PSC (N = 45) and controls (N = 12). Samples from patients with primary biliary cholangitis (PBC) were used as disease controls (N = 20). Results: The levels of hepatic expression of ATXN2, HHEX, PRDX5, MST1, and TNFRSF14 were significantly altered in the PSC group. We focused on the immune-related receptor, TNFRSF14. Immunohistochemistry revealed that TNFRSF14 positivity was significantly higher in biliary epithelia in the PSC group (96 %) than in the control (42 %) and PBC (55 %) groups. High expression of TNFRSF14 was observed only in patients with PSC. Moreover, the expression of LIGHT, which encodes a TNFRSF14-activating ligand, was increased in PSC liver. Immunohistochemistry showed that high expression of LIGHT was more common in PSC biliary epithelia (53 %) than in the PBC (15 %) or control (0 %) groups; moreover, it was positively associated with fibrotic progression. Conclusions: TNFRSF14 and LIGHT are attractive candidate markers for PSC.
- Published
- 2023
46. Pathology Reporting of Gastric Endoscopic Resections: Recommendations From the International Collaboration on Cancer Reporting
- Author
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Chanjuan Shi, Fleur Webster, Iris D. Nagtegaal, Michael J. Bourke, Seung-mo Hong, M. Priyanthi Kumarasinghe, Alfred K. Lam, Gregory Lauwers, Maria O’Donovan, Rachel S. van der Post, Tetsuo Ushiku, Michael Vieth, and Christina Selinger
- Subjects
All institutes and research themes of the Radboud University Medical Center ,Hepatology ,Gastroenterology ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] - Abstract
Item does not contain fulltext 01 juni 2023
- Published
- 2023
47. Immunohistochemistry May Not Replace Immunofluorescence in Paraffin-embedded Tissue for Detecting Masked Monoclonal Immunoglobulin Deposits: A Case Report
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Yasuhiro Oda, Yoichiro Ikeda, Hiroyuki Abe, Akinori Hashiguchi, Kazuhito Hatanaka, Toshihiro Sawai, Tetsuo Ushiku, and Masaomi Nangaku
- Subjects
Internal Medicine ,General Medicine - Published
- 2023
48. Wnt activation-induced disturbance of cell competition causes diffuse invasion of transformed cells through upregulation of NF-κB-mediated MMP21
- Author
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Kazuki Nakai, Hancheng Lin, Shotaro Yamano, Shinya Tanaka, Sho Kitamoto, Kenta Sakuma, Junpei Kurauchi, Eilma Akter, Masamitsu Konno, Jun Koseki, Hirotaka Takahashi, Hideshi Yokoyama, Yukihiro Shiraki, Atsushi Enomoto, Sohei Abe, Yoku Hayakawa, Tetsuo Ushiku, Michihiro Mutoh, Yasuyuki Fujita, and Shunsuke Kon
- Abstract
Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remains unknown. In this study, we examined the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we found that directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. Elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further found that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.
- Published
- 2022
49. Effect of M2-like macrophages of the injured-kidney cortex on kidney cancer progression
- Author
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Taisuke Ishii, Imari Mimura, Koji Nagaoka, Akihiro Naito, Takehito Sugasawa, Ryohei Kuroda, Daisuke Yamada, Yasuharu Kanki, Haruki Kume, Tetsuo Ushiku, Kazuhiro Kakimi, Tetsuhiro Tanaka, and Masaomi Nangaku
- Subjects
Cancer Research ,Cellular and Molecular Neuroscience ,Immunology ,Cell Biology - Abstract
Chronic kidney disease (CKD) affects kidney cancer patients’ mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.
- Published
- 2022
50. Morphologically, genetically and spatially mixed astrocytoma and oligodendroglioma; chronological acquisition of 1p/19q codeletion and CDKN2A deletion: a case report
- Author
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Hirokazu Takami, Akitake Mukasa, Shunsaku Takayanagi, Tsukasa Koike, Reiko Matsuura, Masako Ikemura, Tetsuo Ushiku, Gakushi Yoshikawa, Junji Shibahara, Shota Tanaka, and Nobuhito Saito
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) ,General Medicine - Abstract
"Oligoastrocytoma" disappeared as of the revised fourth edition of the World Health Organization Classification of Tumours of the Central Nervous System, except where appended with "not otherwise specified (NOS)". However, histopathological and genetic backgrounds of cases with dual features of astrocytoma/oligodendroglioma have been sparsely reported. We encountered a 54-year-old man with right frontal glioma comprising two distinct parts on imaging and histopathological examination: grade 4 astrocytoma with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q; and oligodendroglioma with IDH1-R132H, intact ATRX, p53-negativity and partially deleted 1p/19q. At recurrence, histopathology showed low-grade mixed astrocytic and oligodendroglial features: the former with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q and the latter showing IDH1-R132H, intact ATRX, p53-negativity and 1p/19q codeletion. At second recurrence, histopathology was astrocytoma grade 4 with IDH1-R132H, ATRX loss, p53-positivity and intact 1p/19q. Notably, 1p/19q codeletion was acquired at recurrence and CDKN2A was deleted at second recurrence. These findings suggest insights into tumorigenesis: (1) gliomas with two distinct lineages might mix to produce "oligoastrocytoma"; and (2) 1p/19q codeletion and CDKN2A deletion might be acquired during chemo-radiotherapy. Ultimately, astrocytic and oligodendroglial clones might co-exist developmentally or these two lineages might share a common cell-of-origin, with IDH1-R132H as the shared molecular feature.
- Published
- 2022
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